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Development of new sensitive end-points to evaluate the cytotoxicity and genotoxicity of toxicants and environmental pollutants in the nervous system

Objetivo

The main goal of this project is to decide whether modifications of cell signal-transduction and genomic alterations leading to programmed cell death (apoptosis) are responsible for the neurotoxic effects of a heterogeneous group of environmental toxicants. The occurrence of signalling alterations and apoptosis in cultures of neural, lymphoid cells and in tissues from exposed animals will then be used as potential end-points to evaluate neurotoxic effects, in vitro.


The in vitro assessment of biological risks connected with exposure to potentially neurotoxic substances is complicated by the scarce development of sensitive and appropriate model systems and by the lack of sensitive end-points. However, a better understanding of the molecular mechanisms involved in low-level toxicity has provided new information on the cellular targets potentially affected at environmental exposure levels. Sensitive targets may include elements of the signal transduction pathways, including receptors and post-receptor messenger systems, the cytoskeleton, genes involved in growth regulation, differentiation and those responsible for the activation of a self-deletion program known as apoptosis or programmed cell death.

We plan to study whether chemical agents and environmental pollutants can cause modifications of cell signalling and genomic alterations that ensue in neural cell apoptosis at concentrations comparable with in vivo exposure. To identify potential peripheral markers usable for risk assessment in exposed human populations, we will also test the effects of the selected group of compounds in lymphoid cells. We therefore propose a molecular approach to the study of potential cytotoxicity markers in human and animal cell lines, in primary neural cell cultures and in lymphoid cells. The use of these models will allow the identification of early cytotoxic markers, reflecting the in vivo features or a chronic exposure to toxicants. The use of such model systems could then be proposed not only for the study of cytotoxic processes but also for screening tests, following an adequate validation. Thus, we also plan to examine whether the findings obtained in vitro reflect disturbances in development and differentiation of the peripheral and central nervous system in exposed animals. The agents selected for these studies will be within the environmental exposure range. This can ultimately lead to the development of criteria that can be used to predict neurotoxic damage of chemical agents in vivo.

Convocatoria de propuestas

Data not available

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

KAROLINSKA INSTITUTE
Aportación de la UE
Sin datos
Dirección
Nobels Vaeg, 13
171 77 STOCKHOLM
Suecia

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Coste total
Sin datos

Participantes (2)